Clinical presentation of myasthenia gravis

The hallmarks of MG are fluctuation and fatigability (although these are not invariably present). Clinical signs and symptoms usually worsen in the evening and with use of the eyes and may improve with rest. The most common sign of MG is unilateral or bilateral ptosis. The extent of ptosis tends to vary, with the eyelid more ptotic in the evening, after exertion, or after prolonged upward gaze. Cogan eyelid twitch, elicited by having the patient initiate saccades during refixation from downgaze to upgaze, is a brief overelevation of the upper eyelid. Another eyelid sign is enhancement of ptosis; when the more ptotic eyelid is elevated manually, the less ptotic eyelid falls, in keeping with Hering’s law of motor correspondence (equal and simultaneous innervation) (see Chapter 11, Fig 11-3). Fatigue of ptosis can be assessed by asking the patient to sustain upgaze for 1 minute or longer.

MG frequently causes diplopia. The diplopia may be variable, both during the day and from one day to another. The ocular motility pattern may simulate ocular motor CN paresis (usually CN VI or partial, pupil-sparing CN III palsy), internuclear ophthalmoplegia, supranuclear motility disturbances (eg, gaze palsies), or isolated muscle “palsy” (eg, isolated inferior rectus). Total ophthalmoplegia can also occur. Any changing pattern of diplopia, with or without ptosis, should suggest MG. As with ptosis, motility fatigue can also be assessed by having the patient sustain gaze in the direction of paresis. Orbicularis oculi weakness is often present in patients with ocular MG and, if present, can be diagnostically crucial in differentiating MG from other causes of external ophthalmoplegia.

Because the pupil contains muscarinic acetylcholine receptors, pupillary abnormalities are not associated with MG; if abnormalities are present, the clinician should search for another diagnosis. Systemic symptoms and signs that are associated with MG include dysarthria, dysphagia, dyspnea, hoarseness, and weakness in the mastication muscles and in the extensors of the neck, trunk, and limbs. Dysphagia and dyspnea can be life threatening and require prompt treatment. Thyroid eye disease (TED) occurs in about 5% of MG patients. The presence of exotropia and/or ptosis in a patient with TED should raise a concern for superimposed MG.

Diagnosis of myasthenia gravis

The diagnosis of MG is made clinically by identifying typical signs and symptoms, pharmacologically by overcoming the receptor block via the administration of acetylcholinesterase inhibitors, serologically by demonstrating elevated anti–acetylcholine receptor antibody titers or anti–muscle-specific kinase antibodies, and electrophysiologically by electromyography (EMG) results.

If an obvious abnormality is present on examination, results of an edrophonium chloride (a short-acting acetylcholinesterase inhibitor) test, a sleep test, or an ice-pack test can confirm the diagnosis of MG. Edrophonium chloride tests are not commonly performed in eye clinics because rare but serious adverse effects from administration of the drug can occur, including bradycardia, bronchospasm, cholinergic crisis, respiratory arrest, or syncopal episodes. Thus, consultation with the primary physician is suggested before performing the test on patients with a history of cardiac or pulmonary disease. Atropine sulfate (0.4–0.6 mg) should be available immediately in case it is needed. Some physicians pretreat with atropine (0.4 mg subcutaneously) before administering the edrophonium. Patients should also be warned of the possibility of the medication’s short-lived but often discomforting adverse reactions, including fasciculations, sweating, lacrimation, abdominal cramping, nausea, vomiting, and salivation. In most protocols, a small test dose of 2 mg (0.2 mL) edrophonium is first injected intravenously, and the patient is observed for 60 seconds. If the symptoms disappear or decrease (for example, the eyelid elevates or motility improves), the test result is considered positive and can be discontinued. If no response is elicited, additional doses of 4 mg, up to a total of 10 mg, are given. When the ocular symptom is marked (eg, complete ptosis), the endpoint (eyelid elevation) is often dramatic. However, a subtle deficit, such as minimal diplopia, may require use of other means to better define the endpoint. Maddox rod tests with prisms or diplopia fields may be performed before and after edrophonium (see Chapter 7). False-positive responses are rare. A negative test result does not exclude a diagnosis of MG, and repeat testing at a later date may be needed.

An alternative to the edrophonium test is the neostigmine methylsulfate test. This test is particularly useful for children and for adults without ptosis who may require a longer observation period for accurate ocular alignment measurements than that allowed by edrophonium testing. Adverse reactions are similar to those for edrophonium, the most frequent of which are salivation, fasciculations, and gastrointestinal discomfort. Intramuscular neostigmine and atropine are injected concurrently. A positive test result produces improvement of signs within 30–45 minutes.

The sleep test is a safe, simple office test that eliminates the need for edrophonium testing in many patients. After the baseline deficit has been documented (eg, measurements of ptosis, motility disturbance), the patient rests quietly with eyes closed for 30 minutes. The measurements are repeated immediately after the patient “wakes up” and opens his or her eyes. Improvement after rest is highly suggestive of MG.

The ice-packtest is often helpful for diagnosing MG, but only if the patient has ptosis. An ice pack is placed over the patient’s lightly closed eyes for 2 minutes. Improvement of ptosis occurs in most patients with MG (Fig 14-3); however, the cooling effect may be insufficient to overcome the severe weakness in patients with complete myasthenic ptosis.

Other diagnostic tests for MG include electrophysiologic testing and serum assays for anti–acetylcholine receptor (AChR) antibodies or anti–muscle-specific kinase (MuSK) antibodies. There are 3 types of commercially available AChR antibody tests: binding, blocking, and modulating. Tests for binding antibodies are usually requested first, because these highly specific antibodies (near 100% specificity) are detected in approximately 90% of patients with generalized MG and in 50%–70% of patients with ocular MG. Blocking antibodies are rarely present (1%) without binding antibodies. Modulating antibodies are present as frequently as binding antibodies. Blocking and modulating antibody testing is usually reserved for patients who test negative for the binding antibody and for whom MG is still suspected. An assay for MuSK antibodies may confirm an MG diagnosis in some patients who do not have AChR antibodies. MuSK-positive patients tend to have prominent bulbar weakness (eg, dysphagia, dysphonia, chewing difficulties) and will present with purely ocular manifestations only in rare instances.

Figure 14-3 Ice-pack test. A, A 57-year-old woman with myasthenia gravis presented with moderate, variable left ptosis. B, The left ptosis improved after a 2-minute ice-pack test.

(Courtesy of Karl C. Golnik, MD.)

Electromyographic repetitive nerve stimulation shows a characteristic decremental response in many patients with systemic MG. Single-fiber electromyography is most sensitive for MG. All patients with MG should be investigated radiologically for thymomas, which are observed on computed tomography (CT) scans in 10% of these patients. Malignant thymomas are present in a small percentage of patients. Because there is a high coexistence of MG with other autoimmune disorders, serologic testing should be done for thyroid dysfunction and systemic lupus erythematosus.

Gwathmey KG, Burns TM. Myasthenia gravis. Semin Neurol. 2015:35(4):327–339.

Mercelis R, Merckaert V. Diagnostic utility of stimulated single-fiber electromyography of the orbicularis oculi muscle in patients with suspected ocular myasthenia. Muscle Nerve. 2011; 43(2):168–170.

Peeler CE, De Lott LB, Nagia L, Lemos J, Eggenberger ER, Cornblath WT. Clinical utility of acetylcholine receptor antibody testing in ocular myasthenia gravis. JAMA Neurol. 2015; 72(10):1170–1174.

Treatment of myasthenia gravis

Symptomatic, nonpharmacologic treatment for ptosis or diplopia may include use of a patch, a ptosis crutch, or prisms; however, prisms are typically used when the variability is small and with the understanding that the treatment is not always helpful. Pharmacologic treatment for MG includes the use of acetylcholinesterase inhibitors (eg, neostigmine and pyridostigmine), corticosteroids, and other immunosuppressant drugs. Thymectomy is performed in patients with a thymoma and should be considered in patients with generalized MG with or without thymic abnormalities. Short-term therapies such as IVIg or plasmapheresis are occasionally necessary.

MG is a systemic disease with disastrous potential. Although purely ocular MG does exist, systemic MG will develop over the next 2 years in up to 20% of patients who present with ocular MG. Because MG patients may develop respiratory and other life-threatening manifestations, it is prudent to manage their care in cooperation with a neurologist. If ocular signs remain truly isolated for more than 2 years, the disease is likely to remain clinically ocular; nevertheless, late conversion to generalized MG is possible.

Mantegazza R, Bonanno S, Camera G, Antozzi C. Current and emerging therapies for the treatment of myasthenia gravis. Neuropsychiatr Dis Treat. 2011;7:151–160.

Excerpted from BCSC 2020-2021 series: Section 5 - Neuro-Ophthalmology. For more information and to purchase the entire series, please visit https://www.aao.org/bcsc.